Impacts of developmental exposures to the harmful algal bloom toxin domoic acid on neural development and behavior

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Panlilio, Jennifer M.
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Domoic acid
HAB toxins
developmental toxicity
windows of susceptibility
startle response
harmful algal bloom toxins
escape response
Mauthner cells
Harmful algal blooms
Reticulospinal neurons
Mauthner neuron
Oligodendrocyte precursor cells
Neurotoxic agents
Harmful algal blooms (HABs) can produce potent neurotoxins that accumulate in seafood and affect human health. One HAB toxin of concern is domoic acid (DomA), a glutamate analog produced by the marine diatom Pseudo-nitzschia spp. Current regulatory limits are designed to prevent acute neurotoxicity in adult humans. However, research shows that low-level exposure during early life can lead to long-term changes in behavior, neural connectivity, and brain morphology. To determine the underlying mechanisms of developmental toxicity, this dissertation used zebrafish as a tool to: i) Establish the developmental window of susceptibility for DomA toxicity, ii) Characterize the behavioral consequences of exposures, and iii) Identify the cellular targets and processes perturbed by DomA. I found that DomA exposure particularly at 2 days post fertilization (dpf) led to altered startle response behavior, myelination defects, and the downregulation of axonal and myelin structural genes. Using vital dyes and immunolabeling, I assessed DomA-induced alterations in cells required for the startle response. I found no differences in the number of sensory neuromasts or in the sensory cranial ganglia structures that detect the acoustic stimuli. However, the majority of DomA-treated larvae lacked one or both Mauthner cells – hindbrain neurons critical for fast startle responses. DomA-treated larvae also had oligodendrocytes with fewer and shorter myelin sheaths, and appeared to aberrantly myelinate neuronal cell bodies. The loss of the Mauthner neurons and their axons may lead to a cellular environment where oligodendrocytes myelinate neuronal cell bodies in the absence of adequate axonal targets. Indeed, pharmacological treatment that reduced the oligodendrocyte number also led to the reduction in the number of these aberrant, myelinated cell bodies. These results indicate that exposure to DomA at a particular period in neural development targets specific cell types, disrupts myelination in the spinal cord, and leads to prolonged behavioral deficits. These mechanistic insights support hazard assessments of DomA exposures in humans during critical periods in early development.
Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Oceanography and Applied Ocean Science and Engineering at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution June 2019.
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Panlilio, J. M. (2019). Impacts of developmental exposures to the harmful algal bloom toxin domoic acid on neural development and behavior [Doctoral thesis, Massachusetts Institute of Technology and Woods Hole Oceanographic Institution]. Woods Hole Open Access Server.
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